Bolstering the immune system is not a new strategy when trying to protect against deadly pathogens, yet for those individuals that are immunocompromised, this therapeutic approach presents a particular challenge. For instance, while fungal pathogens rarely sicken healthy individuals, the incidence of fungal infections in people with HIV/AIDS or other immune deficiencies has risen sharply in recent years. This population is highly susceptible to fungal infections, resulting in as much as 70% mortality even when treated with antifungal medications.
Now, a new study by investigators at the University of Illinois College of Veterinary Medicine has identified a cellular target that may improve efficacy in vaccines designed to protect immunocompromised individuals from potentially deadly opportunistic infections. Findings from the study were published recently in The Journal of Immunology through an article titled “CBLB Constrains Inactivated Vaccine–Induced CD8+ T Cell Responses and Immunity against Lethal Fungal Pneumonia.”
“Because prevention is better than cure, the ideal solution would be to vaccinate immunocompromised individuals against such opportunistic infections,” notes senior study investigator Som Nanjappa, D.V.M., Ph.D., assistant professor of immunology at the University of Illinois College of Veterinary Medicine. “Currently, however, there are no licensed fungal vaccines. Additionally, in order to be safe for use in immunocompromised patients, such a vaccine would need to be based on an inactivated rather than live pathogen. Yet inactivated vaccines stimulate a weaker immune response.”
The current study, conducted in a mouse model, shows that a protein important in regulating the immune response, called Casitas B-lymphoma-b (CBLB), can be targeted in combination with an inactivated vaccine to elicit immunity through a unique T-cell pathway. This approach may lead to protective vaccines for immune-impaired patients, such as those undergoing chemotherapy, immunosuppressive therapy, or immune deficiency.
The researchers sought to targets that could be used as adjuvants for fungal vaccines. CBLB is a critical negative regulator of T-cell response. Targeting CBLB has been shown to help control chronic viral infections and tumors. The new paper reports on extensive analyses of the role of CBLB in CD8+ T-cell immune response to various live and inactivated vaccines in mouse models that had been depleted of CD4+ T cells.
“We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8+ T-cell responses and immunity to the inactivated vaccine in the absence of CD4+ T cells,” the authors wrote. “In this study, we showed that CBLB, a negative regulator of TCR signaling, suppresses CD8+ T cells in response to inactivated fungal vaccination in a mouse model of CD4+ T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-γ) and type 17 (IL-17A) CD8+ T-cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia.”
CD4+ T cells are required players in almost all the body’s immune responses. The signal activity by other infection-fighting white blood cells, causing B cells to secrete antibodies, macrophages to destroy microbes, and CD8+ T cells (sometimes called cytotoxic or killer T-cells) to kill infected cells. CD4+ T cells also appear to play a critical role in the body’s ability to fight off fungal infections.
Previous work by Dr. Nanjappa and colleagues showed that a live attenuated fungal vaccine could, in the absence of CD4+ T cells, stimulate some CD8+ T cells (type 1 and type 17) to take on some of the function of CD4+ T cells and generate long-term immunity against fungal pathogens in a mouse model.
Data published in the current study support the premise that adjuvants targeting a negative regulator of T-cell response such as CBLB could provide lasting immunity against lethal fungal pathogens in a population deficient in CD4+ T cells. The study also showed that targeting CBLB also invigorates CD8+T-cell response to existing viral infection.
“We showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8+ T cells upon vaccination,” the authors concluded. “Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients.
These findings may have broad translational potential for clinical applications for a variety of immunocompromised conditions, from transplantation and chemotherapy to the immunosuppressive stages of pregnancy.